Induction of ethoxyresorufin-O-deethylase and inhibition of glucocorticoid receptor binding in skin and liver of haired and hairless HRS/J mice by topically applied 2,3,7,8-tetrachlorodibenzo-p-dioxin.
The biochemical changes associated with the toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) have been reported to include alterations in glucocorticoid and epidermal growth factor receptors and mixed function oxidase (MFO) induction. TCDD induces MFO activity in skin of both haired and hairless HRS/J mice. However, epidermal hyperplasia and hyperkeratosis are produced only in the skin of hairless mice. Therefore, since steroid and growth factor responses are implicated in cell proliferation and differentiation, these mice constitute a model system for assessing the possible roles of glucocorticoid and epidermal growth factor receptors in the toxicity of TCDD. The effect of dermal TCDD application (12 micrograms/kg in 100 microliters acetone) on ethoxyresorufin-O-deethylase (EROD) activity, glucocorticoid receptor binding and epidermal growth factor receptors in liver and skin of hairless and haired mice was determined. No differences existed in the basal number of cytosolic glucocorticoid receptors (Bmax) or the apparent equilibrium binding constants (Kd) in control liver, dorsal skin and abdominal skin of male and female hairless mice and haired male mice. Seven days after topical application of TCDD, decreases of approximately 38% were observed in the hepatic Bmax of the glucocorticoid receptors in both haired and hairless mice. However, in dorsal skin, TCDD decreased Bmax by approximately 40% in hairless mice but only 18% in haired mice. The dexamethasone-glucocorticoid receptor complex from both liver and skin of control and TCDD treated mice had similar sedimentation co-efficients in sucrose density gradients. TCDD had no effect on the Kd of glucocorticoid receptors of skin or liver in haired and hairless mice. No difference was observed in the time-dependent increases in hepatic EROD activity between haired and hairless mice after dermal application of TCDD. However, the maximum induction of EROD activity in microsomes from the skin of haired mice was only 60% of the activity observed in hairless animals. The induction of EROD by TCDD did not correlate temporally with the decrease in glucocorticoid receptor binding. The application of TCDD to the skin of hairless mice resulted in epidermal hyperplasia and dermal keratinization, while little change was observed in the general morphology of the skin of haired mice following dermal application. The application of TCDD had no effect on the incidence and distribution of epidermal growth factor receptors in skin of haired and hairless mice as determined immunohistochemically. Thus, the biochemical effects of TCDD are not only strain dependent, but tissue specific. Furthermore, decreases in glucocorticoid and epidermal growth factor receptors do not appear to be general markers of TCDD toxicity.
Stohs
S J
SJ
Systemic Toxicology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709.
Abbott
B D
BD
Lin
F H
FH
Birnbaum
L S
LS
D000818:Animals; D019363:Cytochrome P-450 CYP1A1; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004790:Enzyme Induction; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D007150:Immunohistochemistry; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008297:Male; D051379:Mice; D008812:Mice, Hairless; D010088:Oxidoreductases / Q000096:biosynthesis*; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D011965:Receptors, Glucocorticoid / Q000032:analysis / Q000187:drug effects* / Q000378:metabolism; D012867:Skin / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D014461:Ultracentrifugation
D000072317:Polychlorinated Dibenzodioxins; D011965:Receptors, Glucocorticoid; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; D019363:Cytochrome P-450 CYP1A1; D066246:ErbB Receptors